Instrumented Balance Error Scoring System in Children and Adolescents-A Cross Sectional Study.

Background: The Balance Error Scoring System (BESS) is a commonly used method for clinically evaluating balance after traumatic brain injury. The utilization of force plates, characterized by their cost-effectiveness and portability, facilitates the integration of instrumentation into the BESS protocol. Despite the enhanced precision associated with instrumented measures, there remains a need to determine the clinical significance and feasibility of such measures within pediatric cohorts. Objective: To report a comprehensive set of posturographic measures obtained during instrumented BESS and to examine the concurrent validity, reliability, and feasibility of instrumented BESS in the pediatric point of care setting. Methods: Thirty-seven participants (18 female; aged 13.32 ± 3.31 years) performed BESS while standing on a force plate to simultaneously compute stabilometric measures (instrumented BESS). Ellipse area (EA), path length (PL), and sway velocity (VM) were obtained for each of the six BESS positions and compared with the respective BESS scores. Additionally, the effects of sex and age were explored. A second BESS repetition was performed to evaluate the test-retest reliability. Feedback questionnaires were handed out after testing to evaluate the feasibility of the proposed protocol. Results: The BESS total score was 20.81 ± 6.28. While there was no statistically significant age or sex dependency in the BESS results, instrumented posturography demonstrated an age dependency in EA, VM, and PL. The one-leg stance on a soft surface resulted in the highest BESS score (8.38 ± 1.76), EA (218.78 cm2 ± 168.65), PL (4386.91 mm ± 1859.00), and VM (21.93 mm/s ± 9.29). The Spearman's coefficient displayed moderate to high correlations between the EA (rs = 0.429-0.770, p = 0.001-0.009), PL (rs = 0.451-0.809, p = 0.001-0.006), and VM (rs = 0.451-0.809, p = 0.001-0.006) when compared with the BESS scores for all testing positions, except for the one-leg stance on a soft surface. The BESS total score significantly correlated during the first and second repetition (rs = 0.734, p ≤ 0.001), as did errors during the different testing positions (rs = 0.489-0.799, p ≤ 0.001-0.002), except during the two-legged stance on a soft surface. VM and PL correlated significantly in all testing positions (rs = 0.465-0.675, p ≤ 0.001-0.004; (rs = 0.465-0.675, p ≤ 0.001-0.004), as did EA for all positions except for the two-legged stance on a soft surface (rs = 0.392-0.581, p ≤ 0.001-0.016). A total of 92% of participants stated that the instructions for the testing procedure were very well-explained, while 78% of participants enjoyed the balance testing, and 61% of participants could not decide whether the testing was easy or hard to perform. Conclusions: Instrumented posturography may complement clinical assessment in investigating postural control in children and adolescents. While the BESS score only allows for the consideration of a total score approximating postural control, instrumented posturography offers several parameters representing the responsiveness and magnitude of body sway as well as a more differentiated analysis of movement trajectory. Concise instrumented posturography protocols should be developed to augment neuropediatric assessments in cases where a deficiency in postural control is suspected, potentially stemming from disruptions in the processing of visual, proprioceptive, and/or vestibular information.

Rituximab treatment in pediatric-onset multiple sclerosis.

BACKGROUND AND PURPOSE: Rituximab (RTX) is frequently used off-label in multiple sclerosis. However, studies on the risk-benefit profile of RTX in pediatric-onset multiple sclerosis are scarce. METHODS: In this multicenter retrospective cohort study, patients with pediatric-onset multiple sclerosis from Sweden, Austria and Germany, who received RTX treatment were identified by chart review. Annualized relapse rates, Expanded Disability Status Scale scores and magnetic resonance imaging parameters (new T2 lesions and contrast-enhancing lesions) were assessed before and during RTX treatment. The proportion of patients who remained free from clinical and disease activity (NEDA-3) during RTX treatment was calculated. Side effects such as infusion-related reactions, infections and laboratory abnormalities were assessed. RESULTS: Sixty-one patients received RTX during a median (interquartile range) follow-up period of 20.9 (35.6) months. The annualized relapse rate decreased from 0.6 (95% confidence interval [CI] 0.38-0.92) to 0.03 (95% CI 0.02-0.14). The annual rate of new T2 lesions decreased from 1.25 (95% CI 0.70-2.48) to 0.08 (95% CI 0.03-0.25) and annual rates of new contrast-enhancing lesions decreased from 0.86 (95% CI 0.30-3.96) to 0. Overall, 70% of patients displayed no evidence of disease activity (NEDA-3). Adverse events were observed in 67% of patients. Six patients discontinued treatment due to ongoing disease activity or adverse events. CONCLUSION: Our study provides class IV evidence that RTX reduces clinical and radiological activity in pediatric-onset multiple sclerosis.

5qSMA: standardised retrospective natural history assessment in 268 patients with four copies of SMN2.

Newborn screening for 5qSMA offers the potential for early, ideally pre-symptomatic, therapeutic intervention. However, limited data exist on the outcomes of individuals with 4 copies of SMN2, and there is no consensus within the SMA treatment community regarding early treatment initiation in this subgroup. To provide evidence-based insights into disease progression, we performed a retrospective analysis of 268 patients with 4 copies of SMN2 from the SMArtCARE registry in Germany, Austria and Switzerland. Inclusion criteria required comprehensive baseline data and diagnosis outside of newborn screening. Only data prior to initiation of disease-modifying treatment were included. The median age at disease onset was 3.0 years, with a mean of 6.4 years. Significantly, 55% of patients experienced symptoms before the age of 36 months. 3% never learned to sit unaided, a further 13% never gained the ability to walk independently and 33% of ambulatory patients lost this ability during the course of the disease. 43% developed scoliosis, 6.3% required non-invasive ventilation and 1.1% required tube feeding. In conclusion, our study, in line with previous observations, highlights the substantial phenotypic heterogeneity in SMA. Importantly, this study provides novel insights: the median age of disease onset in patients with 4 SMN2 copies typically occurs before school age, and in half of the patients even before the age of three years. These findings support a proactive approach, particularly early treatment initiation, in this subset of SMA patients diagnosed pre-symptomatically. However, it is important to recognize that the register will not include asymptomatic individuals.

Effects of gene replacement therapy with resamirigene bilparvovec (AT132) on skeletal muscle pathology in X-linked myotubular myopathy: results from a substudy of the ASPIRO open-label clinical trial.

BACKGROUND: X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital muscle disease caused by mutations in the MTM1 gene that result in profound muscle weakness, significant respiratory insufficiency, and high infant mortality. There is no approved disease-modifying therapy for XLMTM. Resamirigene bilparvovec (AT132; rAAV8-Des-hMTM1) is an investigational adeno-associated virus (AAV8)-mediated gene replacement therapy designed to deliver MTM1 to skeletal muscle cells and achieve long-term correction of XLMTM-related muscle pathology. The clinical trial ASPIRO (NCT03199469) investigating resamirigene bilparvovec in XLMTM is currently paused while the risk:benefit balance associated with this gene therapy is further investigated. METHODS: Muscle biopsies were taken before treatment and 24 and 48 weeks after treatment from ten boys with XLMTM in a clinical trial of resamirigene bilparvovec (ASPIRO; NCT03199469). Comprehensive histopathological analysis was performed. FINDINGS: Baseline biopsies uniformly showed findings characteristic of XLMTM, including small myofibres, increased internal or central nucleation, and central aggregates of organelles. Biopsies taken at 24 weeks post-treatment showed marked improvement of organelle localisation, without apparent increases in myofibre size in most participants. Biopsies taken at 48 weeks, however, did show statistically significant increases in myofibre size in all nine biopsies evaluated at this timepoint. Histopathological endpoints that did not demonstrate statistically significant changes with treatment included the degree of internal/central nucleation, numbers of triad structures, fibre type distributions, and numbers of satellite cells. Limited (predominantly mild) treatment-associated inflammatory changes were seen in biopsy specimens from five participants. INTERPRETATION: Muscle biopsies from individuals with XLMTM treated with resamirigene bilparvovec display statistically significant improvement in organelle localisation and myofibre size during a period of substantial improvements in muscle strength and respiratory function. This study identifies valuable histological endpoints for tracking treatment-related gains with resamirigene bilparvovec, as well as endpoints that did not show strong correlation with clinical improvement in this human study. FUNDING: Astellas Gene Therapies (formerly Audentes Therapeutics, Inc.).

Impaired Neurodevelopment in Children with 5q-SMA - 2 Years After Newborn Screening.

OBJECTIVE: Numerous studies have consistently found that reduced SMN protein expression does not severely affect cognitive function in SMA patients. However, the average intelligence quotient of SMA patients has ranged above to below average in different studies. The cognitive development of SMA patients identified through newborn screening remains largely unknown. METHODS: 40 of 47 eligible SMA patients (23 females/17 males) from 39 families identified through newborn screening between January 2018 and December 2020 underwent developmental testing using Bayley III (BSID) after the 2 years of age. The mean age was 29.25 months (23-42 months). 17 patients had 2, 11 patients had 3 and 12 patients had ≥4 copies of SMN2. RESULTS: cognitive scale: mean 94.55 (SD 24.01); language scale: mean 86.09 (SD 26.41); motor scale: 81.28 (SD 28.07). Overall, the cognitive scales show that 14 children were below average, 20 children were average and 6 children were above average. 10/14 children with below average scores had 2 SMN2 copies. The post-hoc pairwise comparisons showed that the cognition main scale was significantly more sensitive to the number of SMN2 copies than the motor main scale of the BSID (MΔ= 10.27, p = 0.014). There is also evidence that cognition scored higher than the language main scale (MΔ= 7.11, p = 0.090). CONCLUSION: The impaired cognitive development of SMA children with 2 SMN2 copies, despite early initiation of therapy, underscores the critical role of the SMN protein in the early stages of brain development.

High-sensitive cardiac troponin I (hs-cTnI) concentrations in newborns diagnosed with spinal muscular atrophy.

Background: Spinal muscular atrophy (SMA) is a genetic neurodegenerative disease leading to muscular weakness and premature death. Three therapeutic options are currently available including gene replacement therapy (GRT), which is potentially cardiotoxic. High-sensitive cardiac troponin I (hs-cTnI) is widely used to monitor potential cardiac contraindications or side effects of GRT, but reference data in healthy newborns are limited and lacking in neonates with SMA. The aim of this study is to determine the range of pre-therapeutic hs-cTnI concentrations in neonates with SMA and to provide guidance for the assessment of these values. Methods: Hs-cTnI levels, genetic and clinical data of 30 newborns (age range 2-26 days) with SMA were retrospectively collected from 6 German neuromuscular centers. In addition, hs-cTnI levels were measured in 16 neonates without SMA. Results: The median hs-cTnI concentration in neonates with SMA was 39.5 ng/L (range: 4-1205). In 16 newborns with SMA, hs-cTnI levels were above the test-specific upper reference limit (URL). Exploratory statistical analysis revealed no relevant correlation between hs-cTnI levels and gender, gestational age, mode of delivery, SMN2 copy number, symptoms of SMA or abnormal cardiac findings. Discussion: Our results suggest higher hs-cTnI plasma levels in newborns with and without SMA compared to assay-specific reference values generated in adults. Given the wide range of hs-cTnI values in neonates with SMA, hs-cTnI levels must be determined before treatment in each patient and post-treatment elevations should be interpreted in the context of the course rather than as individual values.

Safety and efficacy of gene replacement therapy for X-linked myotubular myopathy (ASPIRO): a multinational, open-label, dose-escalation trial.

BACKGROUND: X-linked myotubular myopathy is a rare, life-threatening, congenital muscle disease observed mostly in males, which is caused by mutations in MTM1. No therapies are approved for this disease. We aimed to assess the safety and efficacy of resamirigene bilparvovec, which is an adeno-associated viral vector serotype 8 delivering human MTM1. METHODS: ASPIRO is an open-label, dose-escalation trial at seven academic medical centres in Canada, France, Germany, and the USA. We included boys younger than 5 years with X-linked myotubular myopathy who required mechanical ventilator support. The trial was initially in two parts. Part 1 was planned as a safety and dose-escalation phase in which participants were randomly allocated (2:1) to either the first dose level (1·3 × 1014 vector genomes [vg]/kg bodyweight) of resamirigene bilparvovec or delayed treatment, then, for later participants, to either a higher dose (3·5 × 1014 vg/kg bodyweight) of resamirigene bilparvovec or delayed treatment. Part 2 was intended to confirm the dose selected in part 1. Resamirigene bilparvovec was administered as a single intravenous infusion. An untreated control group comprised boys who participated in a run-in study (INCEPTUS; NCT02704273) or those in the delayed treatment cohort who did not receive any dose. The primary efficacy outcome was the change from baseline to week 24 in hours of daily ventilator support. After three unexpected deaths, dosing at the higher dose was stopped and the two-part feature of the study design was eliminated. Because of changes to the study design during its implementation, analyses were done on an as-treated basis and are deemed exploratory. All treated and control participants were included in the safety analysis. The trial is registered with ClinicalTrials.gov, NCT03199469. Outcomes are reported as of Feb 28, 2022. ASPIRO is currently paused while deaths in dosed participants are investigated. FINDINGS: Between Aug 3, 2017 and June 1, 2021, 30 participants were screened for eligibility, of whom 26 were enrolled; six were allocated to the lower dose, 13 to the higher dose, and seven to delayed treatment. Of the seven children whose treatment was delayed, four later received the higher dose (n=17 total in the higher dose cohort), one received the lower dose (n=7 total in the lower dose cohort), and two received no dose and joined the control group (n=14 total, including 12 children from INCEPTUS). Median age at dosing or enrolment was 12·1 months (IQR 10·0-30·9; range 9·5-49·7) in the lower dose cohort, 31·1 months (16·0-64·7; 6·8-72·7) in the higher dose cohort, and 18·7 months (10·1-31·5; 5·9-39·3) in the control cohort. Median follow-up was 46·1 months (IQR 41·0-49·5; range 2·1-54·7) for lower dose participants, 27·6 months (24·6-29·1; 3·4-41·0) for higher dose participants, and 28·3 months (9·7-46·9; 5·7-32·7) for control participants. At week 24, lower dose participants had an estimated 77·7 percentage point (95% CI 40·22 to 115·24) greater reduction in least squares mean hours per day of ventilator support from baseline versus controls (p=0·0002), and higher dose participants had a 22·8 percentage point (6·15 to 39·37) greater reduction from baseline versus controls (p=0·0077). One participant in the lower dose cohort and three in the higher dose cohort died; at the time of death, all children had cholestatic liver failure following gene therapy (immediate causes of death were sepsis; hepatopathy, severe immune dysfunction, and pseudomonal sepsis; gastrointestinal haemorrhage; and septic shock). Three individuals in the control group died (haemorrhage presumed related to hepatic peliosis; aspiration pneumonia; and cardiopulmonary failure). INTERPRETATION: Most children with X-linked myotubular myopathy who received MTM1 gene replacement therapy had important improvements in ventilator dependence and motor function, with more than half of dosed participants achieving ventilator independence and some attaining the ability to walk independently. Investigations into the risk for underlying hepatobiliary disease in X-linked myotubular myopathy, and the need for monitoring of liver function before gene replacement therapy, are ongoing. FUNDING: Astellas Gene Therapies.

Impaired Brain Growth in Myelin Oligodendrocyte Glycoprotein Antibody-Associated Acute Disseminated Encephalomyelitis.

BACKGROUND AND OBJECTIVES: Acute disseminated encephalomyelitis (ADEM) is the most common phenotype in pediatric myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease. A previous study demonstrated impaired brain growth in ADEM. However, the effect of MOG antibodies on brain growth remains unknown. Here, we performed brain volume analyses in MOG-positive and MOG-negative ADEM at onset and over time. METHODS: In this observational cohort study, we included a total of 62 MRI scans from 24 patients with ADEM (54.2% female; median age 5 years), of which 16 (66.7%) were MOG positive. Patients were compared with healthy controls from the NIH pediatric MRI data repository and a matched local cohort. Mixed-effect models were applied to assess group differences and other relevant factors, including relapses. RESULTS: At baseline and before any steroid treatment, patients with ADEM, irrespective of MOG antibody status, showed reduced brain volume compared with matched controls (median [interquartile range] 1,741.9 cm3 [1,645.1-1,805.2] vs 1,810.4 cm3 [1,786.5-1,836.2]). Longitudinal analysis revealed reduced brain growth for both MOG-positive and MOG-negative patients with ADEM. However, MOG-negative patients showed a stronger reduction (-138.3 cm3 [95% CI -193.6 to -82.9]) than MOG-positive patients (-50.0 cm3 [-126.5 to -5.2]), independent of age, sex, and treatment. Relapsing patients (all MOG positive) showed additional brain volume loss (-15.8 cm3 [-68.9 to 37.3]). DISCUSSION: Patients with ADEM exhibit brain volume loss and failure of age-expected brain growth. Importantly, MOG-negative status was associated with a more pronounced brain volume loss compared with MOG-positive patients.

Improvements in Walking Distance during Nusinersen Treatment - A Prospective 3-year SMArtCARE Registry Study.

BACKGROUND AND OBJECTIVES: Disease progression in patients with spinal muscular atrophy (SMA) has changed dramatically within the past years due to the approval of three different disease-modifying treatments. Nusinersen was the first drug to be approved for the treatment of SMA patients. Clinical trials provided data from infants with SMA type 1 and children with SMA type 2, but there is still insufficient evidence and only scarcely reported long-term experience for nusinersen treatment in ambulant patients. Here, we report data from the SMArtCARE registry of ambulant patients under nusinersen treatment with a follow-up period of up to 38 months. METHODS: SMArtCARE is a disease-specific registry in Germany, Austria and Switzerland. Data are collected as real-world data during routine patient visits. Our analysis included all patients under treatment with nusinersen able to walk independently before start of treatment with focus on changes in motor function. RESULTS: Data from 231 ambulant patients were included in the analysis. During the observation period, 31 pediatric walkers (27.2%) and 31 adult walkers (26.5%) experienced a clinically meaningful improvement of≥30 m in the 6-Minute-Walk-Test. In contrast, only five adult walkers (7.7%) showed a decline in walking distance≥30 m, and two pediatric walkers (1.8%) lost the ability to walk unassisted under treatment with nusinersen. HFMSE and RULM scores improved in pediatric and remained stable in adult patients. CONCLUSION: Our data demonstrate a positive effect of nusinersen treatment in most ambulant pediatric and adult SMA patients. We not only observed a stabilization of disease progression or lack of deterioration, but clinically meaningful improvements in walking distance.

Newbornscreening SMA - From Pilot Project to Nationwide Screening in Germany.

Now that targeted therapies for spinal muscular atrophy are available, attempts are being made worldwide to include screening for spinal muscular atrophy in general newborn screening. In Germany, after pilot projects from 2018-2021, it was included in the general newborn screening from October 2021. To ensure a smooth transition, criteria for follow-up were developed together with key stakeholders. At the beginning of the transition to nationwide screening, false positive findings were reported in 3 patients. After optimization of the screening method in the laboratories concerned, all findings have been subsequently confirmed. On average, the first presentation to a neuromuscular center occurred on day 12 of life, and in patients with 2 or 3 SMN2 copies, therapy started on day 26 of life. Compared with the pilot project, there was no significant delay in timing.

Parental Burden and Quality of Life in 5q-SMA Diagnosed by Newborn Screening.

The aim of this study was to assess the psychosocial burden in parents of children with spinal muscular atrophy (SMA), detected by newborn screening (NBS), for which first pilot projects started in January 2018 in Germany. The survey, performed 1-2 years after children's diagnosis of SMA via NBS, included 3 parent-related questionnaires to evaluate the psychosocial burden, quality of life (QoL)/satisfaction and work productivity and activity impairment in the families. 42/44 families, detected between January 2018 and February 2020, could be investigated. Interestingly, statistical analysis revealed a significant difference between families with children that received SMN-targeted therapy vs. children with a wait-and-see strategy as to social burden (p = 0.016) and personal strain/worries about the future (p = 0.02). However, the evaluation of QoL showed no significant differences between treated vs. untreated children. Fathers of treated children felt more negative impact regarding their productivities at work (p = 0.005) and more negative effects on daily activities (p = 0.022) than fathers of untreated children. Thus, NBS in SMA has a psychosocial impact on families, not only in terms of diagnosis but especially in terms of treatment, and triggers concerns about the future, emphasizing the need for comprehensive multidisciplinary care. Understanding the parents' perspective allows genetic counselors and NBS programs to proactively develop a care plan for parents during the challenging time of uncertainty, anxiety, frustration, and fear of the unknown.

Mechanography in children: pediatric references in postural control.

OBJECTIVE: To establish pediatric age- and sex-specific references for measuring postural control with a mechanography plate in a single centre, prospective, normative data study. METHODS: 739 children and adolescents (396 male/343 female) aged 4 to 17 years were studied. Each participant completed the following test sequence three times: Romberg, semi-tandem, tandem, each with eyes open and closed, and a one-leg stand with eyes open, and a single two-legged jump. Normal ranges were determined based on percentile calculations using the LMS method. Results from the two-legged jump were compared to a reference population the single two-legged jump (s2LJ) assessment in 2013. RESULTS: 38 different equilibrium parameters calculated were analysed. Of all parameters Path Length, vCoFmean, Equilibrium Score and Sway Angle showed a low variation within the same age group but high dependency on age and were thus chosen for automated balance assessment. CONCLUSION: Standard values of postural control in healthy children derived from automated balance testing using a mechanography plate were successfully acquired and a subset of parameters for automated balance assessment identified.

Temporal Dynamics of MOG Antibodies in Children With Acquired Demyelinating Syndrome.

BACKGROUND AND OBJECTIVE: The spectrum of myelin oligodendrocyte glycoprotein (MOG) antibody-associated disorder (MOGAD) comprises monophasic diseases such as acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), and transverse myelitis and relapsing courses of these presentations. Persistently high MOG antibodies (MOG immunoglobulin G [IgG]) are found in patients with a relapsing disease course. Prognostic factors to determine the clinical course of children with a first MOGAD are still lacking. The objective of the study is to assess the clinical and laboratory prognostic parameters for a risk of relapse and the temporal dynamics of MOG-IgG titers in children with MOGAD in correlation with clinical presentation and disease course. METHODS: In this prospective multicenter hospital-based study, children with a first demyelinating attack and complete data set comprising clinical and radiologic findings, MOG-IgG titer at onset, and clinical and serologic follow-up data were included. Serum samples were analyzed by live cell-based assay, and a titer level of ≥1:160 was classified as MOG-IgG-positive. RESULTS: One hundred sixteen children (f:m = 57:59) with MOGAD were included and initially diagnosed with ADEM (n = 59), unilateral ON (n = 12), bilateral ON (n = 16), myelitis (n = 6), neuromyelitis optica spectrum disorder (n = 8) or encephalitis (n = 6). The median follow-up time was 3 years in monophasic and 5 years in relapsing patients. There was no significant association between disease course and MOG-IgG titers at onset, sex, age at presentation, or clinical phenotype. Seroconversion to MOG-IgG-negative within 2 years of the initial event showed a significant risk reduction for a relapsing disease course. Forty-two/one hundred sixteen patients (monophasic n = 26, relapsing n = 16) had serial MOG-IgG testing in years 1 and 2 after the initial event. In contrast to relapsing patients, monophasic patients showed a significant decrease of MOG-IgG titers during the first and second years, often with seroconversion to negative titers. During the follow-up, MOG-IgG titers were persistently higher in relapsing than in monophasic patients. Decrease in MOG-IgG of ≥3 dilution steps after the first and second years was shown to be associated with a decreased risk of relapses. In our cohort, no patient experienced a relapse after seroconversion to MOG-IgG-negative. DISCUSSION: In this study, patients with declining MOG-IgG titers, particularly those with seroconversion to MOG-IgG-negative, are shown to have a significantly reduced relapse risk.

Mitochondrial diseases mimicking autoimmune diseases of the CNS and good response to steroids initially.

INTRODUCTION: Neuroimmunological diseases such as autoimmune encephalitis (AE) or acquired demyelinating syndromes (ADS), can present with neurological symptoms and imaging features that are indistinguishable from mitochondrial diseases (MD) in particular at initial presentation. METHODS: Retrospective analysis of the clinical, laboratory and neuroimaging features of five patients who presented with signs of a neuroimmunological disease but all had pathological pathogenic variants in genes related to mitochondrial energy metabolism. RESULTS: Four patients presented with an acute neurological episode reminiscent of a possible AE and one patient with a suspected ADS at initial presentation. MRI findings were compatible with neuroimmunological diseases in all patients. In two children cerebrospinal fluid (CSF) studies revealed a mildly elevated cell count, two had elevated CSF lactate, none had oligoclonal bands (OCBs). All patients improved rapidly with intravenous steroids or immunoglobulins. Four patients had one or more relapses. Three patients showed worsening of their neurological symptoms with subsequent episodes and one patient died. Relapses in conjunction with new and progressive neurological symptoms, led to additional work-up which finally resulted in different genetic diagnosis of MD in all patients (MT-TL1, MT-ND5, APOA1-BP, HPDL, POLG). DISCUSSION: We would like to draw attention to a subset of patients with MD initially presenting with signs and symptoms mimicking neuroimmunological. Absence of CSF pleocytosis, elevated CSF lactate and progressive, relapsing course should trigger further (genetic) investigations in search of a MD even in patients with good response initially to immunomodulating therapies.

Newborn Screening for SMA - Can a Wait-and-See Strategy be Responsibly Justified in Patients With Four SMN2 Copies?

BACKGROUND: Early treatment after genetic newborn screening (NBS) for SMA significantly improves outcomes in infantile SMA. However, there is no consensus in the SMA treatment community about early treatment initiation in patients with four copies of SMN2. OBJECTIVE: Approach to a responsible treatment strategy for SMA patients with four SMN2 copies detected in newborn screening. METHODS: Inclusion criteria were a history of SMA diagnosed by NBS, age > 12 months at last examination, and diagnosis of four SMN2 copies at confirmatory diagnosis. RESULTS: 21 patients with SMA and four SMN2 copies were identified in German screening projects over a three-year period. In three of them, the SMN2 copy number had to be corrected later, and three patients were lost to follow-up. Eight of the fifteen patients who were subject to long-term follow-up underwent presymptomatic therapy between 3 and 36 months of age and had no definite disease symptoms to date. Five of the other seven patients who underwent a strict follow-up strategy, showed clinical or electrophysiological disease onset between 1.5 and 4 years of age. In two of them, complete recovery was not achieved despite immediate initiation of treatment after the onset of the first symptoms. CONCLUSION: A remarkable proportion of patients with four copies of SMN2 develop irreversible symptoms within the first four years of life, if a wait-and-see strategy is followed. These data argue for a proactive approach, i.e., early initiation of treatment in this subgroup of SMA patients.

INCEPTUS Natural History, Run-in Study for Gene Replacement Clinical Trial in X-Linked Myotubular Myopathy.

BACKGROUND: X-linked myotubular myopathy (XLMTM) is a life-threatening congenital myopathy that, in most cases, is characterized by profound muscle weakness, respiratory failure, need for mechanical ventilation and gastrostomy feeding, and early death. OBJECTIVE: We aimed to characterize the neuromuscular, respiratory, and extramuscular burden of XLMTM in a prospective, longitudinal study. METHODS: Thirty-four participants < 4 years old with XLMTM and receiving ventilator support enrolled in INCEPTUS, a prospective, multicenter, non-interventional study. Disease-related adverse events, respiratory and motor function, feeding, secretions, and quality of life were assessed. RESULTS: During median (range) follow-up of 13.0 (0.5, 32.9) months, there were 3 deaths (aspiration pneumonia; cardiopulmonary failure; hepatic hemorrhage with peliosis) and 61 serious disease-related events in 20 (59%) participants, mostly respiratory (52 events, 18 participants). Most participants (80%) required permanent invasive ventilation (>16 hours/day); 20% required non-invasive support (6-16 hours/day). Median age at tracheostomy was 3.5 months (95% CI: 2.5, 9.0). Thirty-three participants (97%) required gastrostomy. Thirty-one (91%) participants had histories of hepatic disease and/or prospectively experienced related adverse events or laboratory or imaging abnormalities. CHOP INTEND scores ranged from 19-52 (mean: 35.1). Seven participants (21%) could sit unsupported for≥30 seconds (one later lost this ability); none could pull to stand or walk with or without support. These parameters remained static over time across the INCEPTUS cohort. CONCLUSIONS: INCEPTUS confirmed high medical impact, static respiratory, motor and feeding difficulties, and early death in boys with XLMTM. Hepatobiliary disease was identified as an under-recognized comorbidity. There are currently no approved disease-modifying treatments.

Spinal Muscular Atrophy - Is Newborn Screening Too Late for Children with Two SMN2 Copies?

BACKGROUND: Prompt treatment after genetic NBS for SMA substantially improves outcome in infantile SMA. However, deficiency of SMN-protein can cause damage of motor neurons even prior to birth. OBJECTIVE: To describe the neurological status at the time of NBS and the reversibility of neurological deficits in a cohort of patients with only two copies of the SMN2 gene. METHODS: We present motor, respiratory, and bulbar outcomes of 21 SMA patients identified in newborn screening projects in Germany. Inclusion criteria was initiation of SMN targeted medication at less than 6 weeks of age and a minimum age of 9 months at last examination. RESULTS: Twelve patients (57%) developed completely normally, reaching motor milestones in time and having no bulbar or respiratory problems. Three children (14.5%) caught up after initial delay in motor development. Six patients (29%) developed proximal weakness despite early treatment: Three of them (14.5%) achieved the ability to walk with assistance and the other three (14.5%) showed an SMA type 2 phenotype at the age of 16-30 months. One patient (4.8%) had respiratory problems. Three children (14.5%) had mild chewing problems and two individuals (9.5%) needed feeding via gastrotube. Initial CHOP-INTEND values below 30 could be indicative of a less favourable outcome, whereas values above 50 could indicate a good outcome, however in-depth statistic due to the small case number is not predictive. CONCLUSION: More than 70% of SMA patients with two SMN2 copies can achieve independent ambulation with immediate initiation of therapy. However, caregivers and paediatricians must be informed about the possibility of less favourable outcomes when discussing therapeutic strategies.

[Practice-relevant autoimmune diseases of the central nervous system in pediatrics: early diagnosis and adequate initiation of treatment]. / Praxisrelevante autoimmune Erkrankungen des zentralen Nervensystems in der Pädiatrie: frühe Diagnose und adäquater Therapiebeginn.

BACKGROUND: Pediatric autoimmune diseases affecting the central nervous system have recently come into the the focus of attention. Important advances have been made in the field of children with multiple sclerosis (MS), which led to a better understanding of the clinical characteristics and treatment options. Furthermore, new autoantibodies against target antigens of neurons, peripheral nerves and the myelin sheath have been detected. OBJECTIVE: This article summarizes new advances in children with MS and addresses the differences to their adult counterparts. In addition, the most important forms of autoimmune encephalitis, such as N­methyl D­aspartate receptor (NMDA-R) or myelin oligodendrocyte glycoprotein (MOG) encephalitis in children are described together with the diagnostic algorithm and therapeutic approach in the event of a suspected autoimmune encephalitis. Lastly, the clinical spectrum of MOG antibody-associated diseases (MOGAD) is detailed.